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1.
J Dairy Sci ; 104(3): 2935-2955, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33455789

RESUMEN

The objective of this meta-analysis was to quantitatively summarize variations in urea kinetics related to ruminant species, diet composition, and ruminal fermentation. A database of 31 studies measuring urea recycling kinetics were used to derive 2 sets of linear mixed-effects regression models. Study was used as a random intercept and regressions were weighted by 1 divided by the standard error of the mean observation. Models were compared, when appropriated, using the concordance correlation coefficient, root estimated variance associated with study (σˆs) and error (σˆe) and corrected Akaike information criterion values. From a dietary standpoint, most response variables were affected by measures reflecting dietary crude protein [(CP; e.g., N-NH3 or rumen-degradable protein (RDP)] and by variables reflecting dietary energy content [e.g., total digestible nutrients (TDN), dietary starch, or ruminal pH]. Dietary CP, N-NH3, and TDN typically had positive slopes on urea N entry rate (UER; g/d and g/kg0.75), whereas starch and TDN/RDP had negative slopes on UER (g/kg0.75). On the other hand, increasing TDN increased gastrointestinal entry rate (GER; g/kg0.75), whereas an opposite effect was observed for RDP. Increasing diet RDP content reduced the urea N returned to ornithine cycle (ROC; g/kg0.75) in most models. Ruminal variables also reflected the importance of N and energy supplies. Ruminal ammonia concentration significantly affected ROC (g/d and g/kg0.75), used for anabolism (UUA; g/kg0.75), ROC:GER, UUA:GER, and the incorporation of recycled urea N into microbial N relative to gastrointestinal entry rate of urea. Ruminal pH significantly affected GER:UER and ROC:GER ratios. Total digestible nutrients had a positive slope on UUA (g/kg0.75). Increasing the ratio of energy to protein (TDN:RDP) increased the GER:UER ratio, decreased the ROC:GER ratio, and increased the UUA:GER ratio and the incorporation of recycled urea N into microbial N relative to gastrointestinal entry rate of urea N. Comparison among models revealed that species was an important explanatory variable affecting most response variables. However, whether these differences are related to the intrinsic N metabolism of each species or due to the diet variation remains unclear. Understanding these differences could lead to improvements in N use efficiency in ruminant diets by formulating more precise low-N diets considering the particularities for each species.


Asunto(s)
Rumen , Urea , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Proteínas en la Dieta/metabolismo , Digestión , Femenino , Fermentación , Cinética , Lactancia , Nitrógeno/metabolismo , Rumen/metabolismo , Rumiantes/metabolismo , Urea/metabolismo
2.
An Acad Bras Cienc ; 90(4): 3337-3352, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29947672

RESUMEN

The needle test (NT) is a point-of-care test developed in Brazil to evaluate the Phosphorus (P) status in cattle. Based on bone resistance, the NT is a very inexpensive method which allows the diagnosis of any degree of P deficiency in a fast and simple way in vivo and directly on farm. The NT measures three levels of resistance in the transverse process (TP) of the lumbar vertebrae: a) TP that are impenetrable and result in warping of the needle (P healthy animals); b) TP offering some resistance to the penetration (animals with subclinical P deficiency); and c) TP which has minimal resistance to penetration (clinical P deficiency). This manuscript presents results from a series of case studies to evaluate the hypothesis that the NT could be used to assess P status in cattle and assesses the usefulness of results to support decision making on mineral supplementation strategies for grazing cattle. The NT was able to detect the changes in the resistance patterns of the TP, as there was reduction or elevation of P levels in the mineral mixtures. The NT was useful to assist in decision-making for adoption of mineral supplementation strategies better suited for each farm, helping farmers to save money and avoid unnecessary waste of P.


Asunto(s)
Alimentación Animal , Enfermedades de los Bovinos/dietoterapia , Suplementos Dietéticos , Fósforo/administración & dosificación , Fósforo/deficiencia , Agricultura , Animales , Bovinos , Enfermedades de los Bovinos/sangre , Enfermedades de los Bovinos/diagnóstico , Femenino , Masculino
3.
Trop Anim Health Prod ; 50(1): 205-208, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-28918551

RESUMEN

Fertility, weight of calves at weaning, and the economic aspects of a breeding herd receiving mineral supplements containing 75 or 12.5 g of phosphorus (P)/kg were measured from 2013 to 2016. No differences in reproduction parameters or weight at weaning were found before and after the adoption of the new scheme of mineral supplementation. Before the study, the annual cost with the formula containing more P was equivalent to 29.3 weaned beef calves; after the P reduction, the annual cost was equivalent to 2.2 to 6.8 weaned calves. After 3 years of supplementation with 12.5 g P/kg no signs of P deficiency were observed. The clinical-nutritional diagnosis of the herd indicated no cause-effect of P content of mineral supplements upon fertility or performance of healthy cows, demonstranting that the adequate forage allowance was enough to meet most P required by the cows.


Asunto(s)
Alimentación Animal/análisis , Bovinos/fisiología , Dieta/veterinaria , Suplementos Dietéticos , Fósforo/administración & dosificación , Crianza de Animales Domésticos , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Peso Corporal/efectos de los fármacos , Brasil , Cruzamiento , Análisis Costo-Beneficio , Femenino , Fertilidad , Minerales/administración & dosificación , Reproducción , Destete
4.
Science ; 383(6679): 219-225, 2024 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-38207046

RESUMEN

Biodiversity is declining globally, yet many biodiversity hotspots still lack comprehensive species conservation assessments. Using multiple International Union for Conservation of Nature (IUCN) Red List criteria to evaluate extinction risks and millions of herbarium and forest inventory records, we present automated conservation assessments for all tree species of the Atlantic Forest biodiversity hotspot, including ~1100 heretofore unassessed species. About 65% of all species and 82% of endemic species are classified as threatened. We rediscovered five species classified as Extinct on the IUCN Red List and identified 13 endemics as possibly extinct. Uncertainties in species information had little influence on the assessments, but using fewer Red List criteria severely underestimated threat levels. We suggest that the conservation status of tropical forests worldwide is worse than previously reported.


Asunto(s)
Especies en Peligro de Extinción , Extinción Biológica , Bosques , Árboles , Animales , Biodiversidad
5.
Transl Anim Sci ; 8: txae072, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38745851

RESUMEN

The objective of this meta-analysis was to develop and evaluate models for predicting nitrogen (N) excretion in feces, urine, and manure in beef cattle in South America. The study incorporated a total of 1,116 individual observations of N excretion in feces and 939 individual observations of N excretion in feces and in urine (g/d), representing a diverse range of diets, animal genotypes, and management conditions in South America. The dataset also included data on dry matter intake (DMI; kg/d) and nitrogen intake (NI; g/d), concentrations of dietary components, as well as average daily gain (ADG; g/d) and average body weight (BW; kg). Models were derived using linear mixed-effects regression with a random intercept for the study. Fecal N excretion was positively associated with DMI, NI, nonfibrous carbohydrates, average BW, and ADG and negatively associated with EE and CP concentration in the diet. The univariate model predicting fecal N excretion based on DMI (model 1) performed slightly better than the univariate model, which used NI as a predictor variable (model 2) with a root mean square error (RMSE) of 38.0 vs. 39.2%, the RMSE-observations SD ratio (RSR) of 0.81 vs. 0.84, and concordance correlation coefficient (CCC) of 0.53 vs. 0.50, respectively. Models predicting urinary N excretion were less accurate than those derived to predict fecal N excretion, with an average RMSE of 43.7% vs. 37.0%, respectively. Urinary and manure N excretion were positively associated with DMI, NI, CP, average BW, and ADG and negatively associated with neutral detergent fiber concentration in the diet. As opposed to fecal N excretion, the univariate model predicting urinary N excretion using NI (model 10) performed slightly better than the univariate model using DMI (model 9) as predictor variable with an RMSE of 36.0% vs. 39.7%, RSR 0.85 vs. 0.93, and CCC of 0.43 vs. 0.29, respectively. The models developed in this study are applicable for predicting N excretion in beef cattle across a broad spectrum of dietary compositions and animal genotypes in South America. The univariate model using DMI as a predictor is recommended for fecal N prediction, while the univariate model using NI is recommended for predicting urinary and manure N excretion because the use of more complex models resulted in little to no benefits. However, it may be more useful to consider more complex models that incorporate nutrient intakes and diet composition for decision-making when N excretion is a factor to be considered. Three extant equations evaluated in this study have the potential to be used in tropical conditions typical of South America to predict fecal N excretion with good precision and accuracy. However, none of the extant equations are recommended for predicting urine or manure N excretion because of their high RMSE, and low precision and accuracy.

6.
Toxins (Basel) ; 16(2)2024 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-38393161

RESUMEN

Snake venoms have evolved in several families of Caenophidae, and their toxins have been assumed to be biochemical weapons with a role as a trophic adaptation. However, it remains unclear how venom contributes to the success of venomous species for adaptation to different environments. Here we compared the venoms from Bothrocophias hyoprora, Bothrops taeniatus, Bothrops bilineatus smaragdinus, Bothrops brazili, and Bothrops atrox collected in the Amazon Rainforest, aiming to understand the ecological and toxinological consequences of venom composition. Transcriptomic and proteomic analyses indicated that the venoms presented the same toxin groups characteristic from bothropoids, but with distinct isoforms with variable qualitative and quantitative abundances, contributing to distinct enzymatic and toxic effects. Despite the particularities of each venom, commercial Bothrops antivenom recognized the venom components and neutralized the lethality of all species. No clear features could be observed between venoms from arboreal and terrestrial habitats, nor in the dispersion of the species throughout the Amazon habitats, supporting the notion that venom composition may not shape the ecological or toxinological characteristics of these snake species and that other factors influence their foraging or dispersal in different ecological niches.


Asunto(s)
Bothrops , Venenos de Crotálidos , Serpientes Venenosas , Animales , Proteómica , Bosque Lluvioso , Venenos de Crotálidos/química , Antivenenos , Serpientes
7.
J Bone Miner Metab ; 31(4): 449-54, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23515922

RESUMEN

Recent evidence suggests that changes in plasma levels of osteopontin (OPN) may be a promising marker for early diagnosis of bone disorders. We hypothesized that a frequent OPN gene polymorphism may be useful for identifying very old individuals with alterations in plasma OPN levels and consequently at risk of abnormal bone density scores. Men and women (80 years or older) living in the Brazilian Federal District underwent assessments with dual energy X-ray absorptiometry for bone mineral density (BMD) of the femoral neck, femoral head and lumbosacral (L1 to S5) regions. Clinical inspection was performed to assess other physical traits and to exclude co-morbidities (cardiovascular, autoimmunity, infections or neoplastic diseases). Serum concentrations of OPN were determined with an enzyme-linked immunosorbent assay, whereas the A7385G polymorphism (rs1126772) was determined by direct sequencing of a polymerase chain reaction product. Among the two hundred and ten subjects enrolled, no differential scores for bone mineral density could be observed across genotypes, but a greater content of circulating OPN was found among carriers of the A allele (P ≤ 0.05) even after adjustments. Serum OPN levels were negatively correlated with femoral neck density (P = 0.050 for BMD; P = 0.032 for T scores) but not with scores of the other regions investigated. Analyses with the sample dichotomized to age and body mass revealed that this inverse relationship was noticeable only among those aged within the highest and weighing within the lowest intervals. Our findings indicate elevated circulating osteopontin levels in patients with decreased bone mineral density, consistent with a modest contribution of an OPN allelic variation to its expression. Assessing the clinical relevance of our findings demands forthcoming studies.


Asunto(s)
Densidad Ósea/genética , Osteopontina/genética , Anciano de 80 o más Años , Antropometría , Índice de Masa Corporal , Brasil , Femenino , Humanos , Masculino , Osteopontina/sangre , Polimorfismo de Nucleótido Simple/genética
8.
Neuroimmunomodulation ; 20(5): 239-46, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23838435

RESUMEN

BACKGROUND: Single-nucleotide polymorphisms in genes encoding immunological mediators can affect the biological activity of these molecules by regulating transcription, translation, or secretion, modulating the genetic risk of inflammatory damage in Alzheimer's disease (AD). Nonetheless, the Brazilian contingent is highly admixed, and few association trials performed herein with AD patients have considered genetic ancestry estimates as co-variables when investigating markers for this complex trait. METHODS: We analyzed polymorphisms in 10 inflammatory genes and compared the genotype distribution across outpatients with late-onset AD and noncognitively impaired subjects from Midwest Brazil under a strict criterion, and controlling for ancestry heritage and ApoE genotype. RESULTS: Our findings show an almost 40% lower chance of AD (p = 0.004) among homozygotes of the IL10 -1082A allele (rs1800896). Dichotomization to ApoE and mean ancestry levels did not affect protection, except among those with greater European or minor African heritage. CONCLUSION: The IL10 locus seems to affect the onset of AD in a context sensitive to the genetic ancestry of Brazilian older adults.


Asunto(s)
Enfermedad de Alzheimer/genética , Citocinas/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Brasil , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
9.
ACS Infect Dis ; 9(6): 1267-1282, 2023 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-37167453

RESUMEN

Acetylation signaling pathways in trypanosomatids, a group of early branching organisms, are poorly understood due to highly divergent protein sequences. To overcome this challenge, we used interactomic datasets and AlphaFold2 (AF2)-multimer to predict direct interactions and validated them using yeast two and three-hybrid assays. We focused on MORF4 related gene (MRG) domain-containing proteins and their interactions, typically found in histone acetyltransferase/deacetylase complexes. The results identified a structurally conserved complex, TcTINTIN, which is orthologous to human and yeast trimer independent of NuA4 for transcription interaction (TINTIN) complexes; and another trimeric complex involving an MRG domain, only seen in trypanosomatids. The identification of a key component of TcTINTIN, TcMRGBP, would not have been possible through traditional homology-based methods. We also conducted molecular dynamics simulations, revealing a conformational change that potentially affects its affinity for TcBDF6. The study also revealed a novel way in which an MRG domain participates in simultaneous interactions with two MRG binding proteins binding two different surfaces, a phenomenon not previously reported. Overall, this study demonstrates the potential of using AF2-processed interactomic datasets to identify protein complexes in deeply branched eukaryotes, which can be challenging to study based on sequence similarity. The findings provide new insights into the acetylation signaling pathways in trypanosomatids, specifically highlighting the importance of MRG domain-containing proteins in forming complexes, which may have important implications for understanding the biology of these organisms and developing new therapeutics. On the other hand, our validation of AF2 models for the determination of multiprotein complexes illuminates the power of using such artificial intelligence-derived tools in the future development of biology.


Asunto(s)
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Humanos , Inteligencia Artificial , Furilfuramida , Núcleo Celular/metabolismo , Proteínas , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Histona Acetiltransferasas/genética
10.
Dement Geriatr Cogn Disord ; 33(5): 311-7, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22759767

RESUMEN

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia worldwide, and bears remarkable evidence for a differential prevalence among continental populations. In this scenario, estimating ancestry proportions in recently admixed populations is a strategy that can help increasing knowledge about the genetic structure of this complex trait. AIM/METHODS: Our purpose was to assess mean ancestry estimates for the three main parental contributors to the Brazilian contingent (European, African and Amerindian) using a panel of 12 ancestry informative markers. Outpatients with the late-onset form of AD (n = 120) were compared for ancestry levels with non-cognitively impaired subjects (n = 412) in the Midwest Brazil, controlling for classic clinical, social and anthropometric risk factors. RESULTS: Our findings show a 3-fold greater genetic Amerindian content among control subjects compared to AD patients (p < 0.001). CONCLUSION: Our results suggest that the allelic architecture of Native Americans can confer protection against the onset of the disease.


Asunto(s)
Enfermedad de Alzheimer/genética , Población Negra/genética , Indígenas Sudamericanos/genética , Población Blanca/genética , Anciano , Anciano de 80 o más Años , Apolipoproteína E4/genética , Brasil , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
11.
J Anim Sci ; 100(5)2022 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-35311895

RESUMEN

This study aimed to evaluate the use of total odd-chain fatty acids (OCFA) as a marker to estimate microbial nitrogen flow (MicN) and calculate the efficiency of microbial nitrogen synthesis (EMNS) in Nellore steers fed high-concentrate diets supplemented with different nitrogen supplements (NS). Ruminally and duodenally cannulated Nellore steers (n = 6; 354 ± 12 kg) were used in a 6 × 6 repeated switchback design balanced for residual effects. Treatments were arranged in a 3 × 3 factorial of three nitrogen (N) supplements (urea plus soybean meal; corn gluten meal; dried distillers' grains plus solubles) and three microbial markers (OCFA; double-labeled urea, 15N; microbial nucleic acid bases, MNAB). The total mixed ration was composed of fresh chopped sugarcane as the forage source in an 83:17 concentrate: forage ratio (dry matter basis). Linear regression was used to develop predictions of MicN from OCFA using 15N and MNAB as response variables. Microbial N flow was underestimated by the MNAB marker compared to 15N. Neither NS nor their respective interactions with the marker methods (MM) affected MicN or EMNS (P > 0.05). However, MicN was different for 15N and MNAB (P > 0.001 for both treatments). Marker methods affected EMNS in all energetic bases (total digestible carbohydrates P < 0.001; rumen-fermentable carbohydrates P < 0.001; organic matter truly degradable in the rumen P < 0.001). Equations that utilized OCFA as a regressor to predict MicN under different MM resulted in good fits of the data as observed by the coefficient of determination (R2; 15N = 0.78; MNAB = 0.69). Microbial N flow estimated from OCFA was overpredicted (15N by 7.46%; MNAB by 4.30%) compared with observed values. The OCFA model presented a small slope bias when methodological validation was applied (15N = 0.96%; MNAB = 3.90%), ensuring reliability of the proposed alternative method. Based on the conditions of this experiment, OCFA may be a suitable alternative to other methods that quantify MicN under different dietary conditions.


Nutritional strategies that maximize microbial nitrogen supply to the small intestine may improve cattle performance. Nevertheless, in vivo quantification generally requires sensitive or expensive methods and often yields highly variable results. In the present work, we investigated the use of duodenal odd-chain fatty acids (OCFA) as an alternative method to predict microbial nitrogen flow (MicN) and calculated its efficiency on different energetic bases under different dietary nitrogen supplements. We utilized total OCFA flow (TOCFAf) to predict MicN by two well-established conventional methods: 1) 15N, considered the gold standard and 2) microbial nucleic acid bases. Models presented a positive relationship between TOCFDf and response variables, and under validation, both demonstrated low estimation bias. Under the conditions of this experiment, OCFA appeared to serve as an alternative marker to quantify ruminal MicN for beef cattle.


Asunto(s)
Nitrógeno , Rumen , Alimentación Animal/análisis , Animales , Carbohidratos , Dieta/veterinaria , Digestión , Ácidos Grasos/metabolismo , Fermentación , Nitrógeno/metabolismo , Reproducibilidad de los Resultados , Rumen/metabolismo , Urea/metabolismo
12.
Neuroimmunomodulation ; 18(3): 165-70, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21311202

RESUMEN

OBJECTIVE: The increase in inflammatory activity associated with aging is a characteristic of chronic disease processes that accounts for most of the mortality in the elderly. Resistance training (RT) has been shown to promote metabolic and functional benefits in this population. The objective of this study was to investigate the association between long-term RT and circulating levels of the proinflammatory mediators IL-6, TNF-α and IFN-γ in elderly women. METHODS: This cross-sectional study included 54 older outpatients divided into a group that underwent RT (n = 28) for an average of 8.6 ± 0.3 months and a sedentary group (n = 26). Measurements were taken only at the end of the intervention, and cytokine values were log-transformed. Dietary intake was controlled as a confounding factor. RESULTS: The RT group presented reduced levels of log10IFN-γ (approx. 45%; p = 0.003), log10IL-6 (approx. 30%; p = 0.002) and log10TNF-α (approx. 22%; p = 0.036). Total caloric intake and systolic arterial blood pressure were significantly lower in the RT group (p = 0.001 and p = 0.022, respectively). Pearson's product moment correlation test revealed a negative association between the fat-free mass (FFM) index and log-transformed IL-6 levels (p = 0.03; n = 54) and a trend towards significance for the correlation between the FFM index and log10IFN-γ (p = 0.05; n = 54). CONCLUSION: Long-term, moderate-intensity RT in elderly women is associated with lower circulating levels of cytokines that are potentially implicated in disorders associated with physical inactivity and aging.


Asunto(s)
Citocinas/sangre , Terapia por Ejercicio , Tolerancia Inmunológica/fisiología , Inflamación/sangre , Inflamación/terapia , Entrenamiento de Fuerza , Anciano , Estudios Transversales , Terapia por Ejercicio/métodos , Femenino , Humanos , Inflamación/inmunología , Mediadores de Inflamación/sangre , Interferón gamma/sangre , Interleucina-6/sangre , Entrenamiento de Fuerza/métodos , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangre
13.
Animals (Basel) ; 11(12)2021 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-34944293

RESUMEN

Immediate and short-term changes in diet composition can support individualized, real-time interventions in precision dairy production systems, and might increase feed efficiency (FE) of dairy cattle in the short-term. The objective of this study was to determine immediate and short-term effects of changes in diet composition on production parameters of dairy cattle fed varying amounts of top dressed commodities. A 4 × 4 replicated Latin square design was used to evaluate responses of twenty-four Holstein cows fed either no top dress (Control) or increasing amounts of: corn grain (CG), soybean meal (SBM), or chopped mixed grass hay (GH) top dressed on a total mixed ration (TMR) over four, 9-day periods. Throughout each period, top dressed commodities were incrementally increased, providing 0% to 20% of calculated net energy of lactation (NEL) intake. Measured production responses were analyzed for each 9-d period using a mixed-effects model considering two different time ranges. Samples collected from d 3 and 4 and from d 7 and 8 of each period were averaged and used to reflect "immediate" vs. "short-term" responses, respectively. In the immediate response time frame, control fed cows had lower milk yield, milk fat yield, and milk true protein yield than CG and SBM supplemented animals but similar responses to GH supplemented animals. Milk fat and protein percentages were not affected by top dress type in the immediate term. In the short-term response time-frame, GH supplemented animals had lower DMI and milk fat yield than all other groups. Control and GH supplemented cows had lower milk yield than CG and SBM fed cows. In the immediate response time frame, FE of SBM supplemented cows was superior to other groups. In the short-term time frame, FE of GH and SBM groups was improved over the control group. Results suggest that lactating dairy cows show rapid performance responses to small (<20% NEL) changes in dietary composition, which may be leveraged within automated precision feeding systems to optimize efficiency of production. Before this potential can be realized, further research is needed to examine integration of such strategies into automatic feeding systems and downstream impacts on individual animal FE and farm profitability.

14.
Eur J Cancer ; 158: 63-71, 2021 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-34655838

RESUMEN

BACKGROUND: Androgen deprivation therapy (ADT) combined with apalutamide, abiraterone acetate plus prednisone, enzalutamide, or docetaxel are the standard treatments for advanced castration-sensitive prostate cancer (CSPC). We investigated ADT-free alternatives for advanced CSPC. PATIENTS AND METHODS: LACOG 0415 is a phase 2, open-label, non-comparative, randomized trial. Patients with advanced CSPC were randomized (1:1:1) to receive goserelin plus abiraterone acetate and prednisone (ADT plus AAP arm), apalutamide (APA arm), or apalutamide plus abiraterone acetate and prednisone (APA plus AAP arm). The primary endpoint was the proportion of patients with PSA of ≤0.2 ng/mL at week 25 in the modified intention-to-treat population. Safety analyses were performed in all patients with at least one dose of the study drug. RESULTS: Of 128 randomized patients, 120 patients were evaluable for PSA response at week 25; 17.2% had a high-risk biochemical recurrence, 8.6% had locally advanced disease, and 74.2% had distant metastases. At week 25, PSA of ≤0.2 ng/mL was observed in 75.6% (95%CI 59.7%-87.6%), 60.0% (95%CI 43.3%-75.1%), and 79.5% (95%CI 63.5%-90.7%) of patients in ADT plus AAP, APA, and APA plus AAP arms, respectively. PSA decline of ≥80% was observed in 100%, 90.0%, and 97.4%, respectively. Grade 3-4 AEs were observed in 31.0%, 21.4% and 36.4%, respectively. Testosterone levels increased significantly in the APA arm and decreased significantly in ADT plus AAP and APA plus AAP arms. CONCLUSIONS: ADT-free alternatives provide a high PSA response in advanced CSPC, although the APA arm did not reach the expected rate of PSA of ≤0.2 ng/mL at week 25. These results warrant further investigation of ADT-free treatments as alternatives in advanced CSPC. SOURCE STUDY REGISTRATION: ClinicalTrials.govNCT02867020.

15.
J Biomol Struct Dyn ; 37(11): 2960-2969, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30058445

RESUMEN

In this work, we combined molecular modeling, computational docking and in vitro analysis to explore the antileishmanial effect of some resveratrol analogs (ResAn), focusing on their pro-oxidant effect. The molecular target was the trypanothione reductase of Leishmania braziliensis (LbTryR), an essential component of the antioxidant defenses in trypanosomatid parasites. Three-dimensional structures of LbTryR were modeled and molecular docking studies of ResAn1-5 compounds showed the following affinity: ResAn1 > ResAn2 > ResAn4 > ResAn5 > ResAn3. Positive correlation was observed between these compounds' affinity to the LbTryR and the IC50 values against Leishmania sp (ResAn1 < ResAn2 < ResAn4), which allows for TryR being considered an important target for them. As the compound ResAn1 showed the best antileishmanial activity, and docking studies showed its high affinity for NADP binding site (NS) of TryR, plus having been able to induce ROS production in L. braziliensis promastigotes treated, ResAn1 probably occupies NS interfering in the electron transfer processes responsible for the catalytic reaction. The in silico prediction of ADMET properties suggests that ResAn1 may be a promising drug candidate with properties to cross biological membranes and high gastrointestinal absorption, not violating Lipinski's rules. Ultimately, the antileishmanial effect of ResAn can be associated with a pro-oxidant effect which, in turn, can be exploited as an antimicrobial agent. Communicated by Ramaswamy H. Sarma.


Asunto(s)
Antiprotozoarios/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Leishmania braziliensis/efectos de los fármacos , Leishmania braziliensis/enzimología , Leishmaniasis/tratamiento farmacológico , NADH NADPH Oxidorreductasas/metabolismo , Resveratrol/química , Animales , Antioxidantes/química , Antioxidantes/farmacología , Antiprotozoarios/química , Sitios de Unión , Leishmaniasis/parasitología , Macrófagos/efectos de los fármacos , Macrófagos/enzimología , Macrófagos/parasitología , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , NADH NADPH Oxidorreductasas/química , Conformación Proteica , Proteínas Protozoarias/química , Proteínas Protozoarias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Resveratrol/farmacología , Relación Estructura-Actividad
16.
Clin Chim Acta ; 396(1-2): 70-5, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18657531

RESUMEN

BACKGROUND: Since variations on the renin angiotensin (RA) system tend to exert effects on blood pressure, we investigated the association of the common ACE and AT1R polymorphisms with response to a multivariate pharmacotherapy. METHODS: This prospective study involved 169 hypertensive, community-dwelling older women. Genotypes were obtained by length analysis or direct sequencing of PCR products. Blood pressure-lowering pharmacotherapy was conducted according to current Brazilian Guidelines on Hypertension. RESULTS: Genotype frequencies were in agreement to the Hardy-Weinberg equilibrium. Interventions were found to represent actual hypertension-management practices in Brazil, and accounted for a significant reduction in both systolic (P<0.001) and diastolic (P<0.001) blood pressure. Concerning the effect of polymorphisms, no influence of the ACE and AT1R genotypes were found on the magnitude of the treatment-induced blood pressure reduction (P>0.05). Nonetheless, the clinical result varied according to the ACE alleles since mean systolic pressure was roughly 10 mm Hg higher in insertion (I) homozygotes than in the deletion (D) counterparts either in baseline (P=0.001) and endpoint (P=0.010). CONCLUSION: The outcome of the antihypertensive pharmacotherapy advocated by national guidelines was significantly influenced by the ACE I/D polymorphism but not by the AT1R 1166 A/C polymorphism among postmenopausal women.


Asunto(s)
Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Polimorfismo Genético/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/genética , Anciano , Presión Sanguínea/efectos de los fármacos , Brasil/epidemiología , Femenino , Genotipo , Humanos , Hipertensión/epidemiología , Hipertensión/fisiopatología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Receptor de Angiotensina Tipo 1/genética , Resultado del Tratamiento
19.
Clinics (Sao Paulo) ; 71(12): 725-732, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-28076518

RESUMEN

OBJECTIVES:: The number of deaths from vascular diseases is incredibly high worldwide, and reliable markers for major events are still needed. The current cross-sectional study investigated the association of Klotho haplotypes and Klotho serum levels with classic risk factors and a clinical history of vascular events. METHODS:: Clinical, anthropometric, biochemical and nutritional assessments were conducted with 168 older adults, complemented by genotyping (rs9536314 and rs9527025) and the detection of serum Klotho (ELISA). RESULTS:: Klotho levels and haplotypes did not associate with most classic risk factors for vascular events, including markers such as C-reactive protein and homocysteine. A positive association was only found between Klotho levels and the previous occurrence of a myocardial infarction by both correlational (p=0.006) and variance analyses (p<0.001), and these associations were independent of the context. CONCLUSION:: Our results suggest that serum Klotho is higher in individuals with a clinical history of myocardial infarction but not with a history of coronary artery disease or stroke. None of the Klotho haplotypes were associated with the variables investigated herein.


Asunto(s)
Glucuronidasa/sangre , Glucuronidasa/genética , Infarto del Miocardio/sangre , Factores de Edad , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Antropometría , Biomarcadores/sangre , Proteína C-Reactiva/análisis , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/genética , Estudios Transversales , Ingestión de Energía , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnicas de Genotipaje , Haplotipos , Homocisteína/sangre , Humanos , Proteínas Klotho , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Evaluación Nutricional , Valores de Referencia , Factores de Riesgo , Factores Sexuales , Estadísticas no Paramétricas , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/genética
20.
Front Physiol ; 7: 260, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27445850

RESUMEN

The aim of this study was to investigate the effects of two consecutive Crossfit® training sessions (24 h apart) designed to enhance work-capacity that involved both cardiovascular and muscular exercises on cytokines, muscle power, blood lactate and glucose. Nine male members of the CrossFit® community (age 26.7 ± 6.6 years; body mass 78.8 ± 13.2 kg; body fat 13.5 ± 6.2%; training experience 2.5 ± 1.2 years) completed two experimental protocols (24 h apart): (1) strength and power exercises, (2) gymnastic movements, and (3) metabolic conditioning as follows: 10 min of as many rounds as possible (AMRAP) of 30 double-unders and 15 power snatches (34 kg). The same sequence as repeated on session 2 with the following metabolic conditioning: 12 min AMRAP of: row 250 m and 25 target burpees. Serum interleukin-6 (IL-6), IL-10, and osteoprotegerin were measured before, immediately post and 24 h after workout of the day (WOD) 1, immediately post, 24 and 48 h after WOD 2. Peak and mean power were obtained for each repetition (back squat with 50% of 1 repetition maximum) using a linear position transducer measured before, immediately post and 24 h after WOD 1, immediately post and 24 h after WOD 2. Blood lactate and glucose were measured pre and immediately post WOD 1 and 2. Although both sessions of exercise elicited an significant increase in blood lactate (1.20 ± 0.41 to 11.84 ± 1.34 vs. 0.94 ± 0.34 to 9.05 ± 2.56 mmol/l) and glucose concentration (81.59 ± 10.27 to 114.99 ± 12.52 vs. 69.47 ± 6.97 to 89.95 ± 19.26 mg/dL), WOD 1 induced a significantly greater increase than WOD 2 (p ≤ 0.05). The training sessions elicited significant changes (p ≤ 0.05) in IL-6, IL-10 and osteoprotegerin concentration over time. IL-6 displayed an increase immediately after training WOD 1 [197 ± 109%] (p = 0.009) and 2 [99 ± 58%] (p = 0.045). IL-10 displayed an increase immediately after only WOD 1 [44 ± 52%] (p = 0.046), and decreased 24 and 48 h following WOD 2 (~40%; p = 0.018) as compared to pre-exercise values. Osteoprotegerin displayed a decrease 48 h following WOD 2 (~25%; p = 0.018) as compared with pre intervention. In conclusion, two consecutive Crossfit® training sessions increase pro/anti-inflammatory cytokines with no interference on muscle performance in the recovery period.

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